2-(p-amino-benzenesulfonamido)-4-methyl-5-hydroxyethyl thiazole



Patented Dec. 30, 1947 2 (p smo-nimznmssmrommnol 4 marm-s-nrnaoxrnrm'rnmzom George Newbery, Hutton Mo'unt, England, as-

signor, by niesne assignments, to Merck 8: Co. Inc., Railway, N. 1.,a'corporation of New J ersey No Drawing. Original application May 29,1939, Serial No. 276,416. Divided and this application May 5, 1945,Serial No. 592,280. In Great Britain, Australia, Barbados, Denmark,Finland, India, New Zealand, Norway, Sweden, and

Canada, JnneB, 1938 v 1 Claim. (Cl. 260239.6)

This application is a division of Serial No. 276,-

- 416 filed on May 29, 1939, now Patent Number 2,362,087. a The presentinvention relates to the preparation of 2-(p-amino-benzene-sulphonamido)derivatives of thiazole and benzthiazole and their substitutedderivatives, many of which have been found to be of therapeuticimportance, and has for its object the preparation of substitutedpamino-benzene-sulphonamido derivatives of thiazole' and benzthiazole ofthe general formula -nmcsmsomaa in which R=hydrogen or an alkyl oraralkyl group and R is a thiazole residue S-CH or a benzthiazoleresiduein which one or more of-the hydrogen atoms maybe substituted by any ofthe following groups i 2 (B) Derivatives in which R is alkyl or aralkylmay be obtained by the action of alkyl sulphates on the aminoderivatives obtained by any of the methods described in paragraph A orby the action of alkyl or aralkyl halides or alkyl sulphates on theintermediate condensation products obtained as described in paragraph Aand subsequently converting the acylamino group by hydrolysis, thenitro' or azo groups by reduction or the halogen groups by ammonia tocompounds of the type p-NHzCsHfiOaNRR.

(C) In place of the compounds p-XCcI-RSOzCl the anhydrides (D-XCSHiSOQZOor the bromides p-XCtH4SOzBr may also be used.

The following examples illustratehow the invention may be carried out inpractice, but it is to be understood that the invention is in no wayAccording to the present invention these compounds may be prepared bymethods which are summarised as follows:

(A) Derivatives in which R=hydrogen may be prepared by condensingcompounds of the type D-XCsHtY with compounds of the type ZR in which Ris a thiazole or benzthiazole residue (when Y is SOzCl, Z is NH, andwhenY is SOzNHz, Z is a halogen) to form compound of the typep-XCsH4SOzNI-IR which can readily be converted into compounds of thetype radicle, or a halogen, which groups may readily be converted to anamino group, by hydrolysis in l the .first case, by reduction in thesecond and third cases or by the action of ammonia in the fourth case.

limited to the details given in these examples.

Emample I 50 grammes of 2-amino-thiazole are dissolved in 200 c. c. ofanhydrous pyridine and a slight excess (130 grammes) of dryp-acetylamino-benzene-sulphonyl chloride is slowly added. Some heatisproduced and when the mixture begins to cool it is heated for a fewminutes to complete the reaction and a large volume of water is added.The precipitated oily 2-(p-acetyl-aminobenzene sulphonamido) thiazolequickly solidifies and is crystallised from solution in warm causticsoda by acidification with 50% acetic acid. The purifled product meltsat 256 C.

For hydrolysis the product is taken up in a volume of 2N caustic sodaequal to 10 times its weight and the mixture heated at C. for an hour.Concentrated hydrochloric acid is then added until the solid at firstprecipitated has'redissolved. The solution is treated with charcoal,filtered and the requisite 2(p-amino benzene sulphonamido) thiazole M.Pt. 196-197 C. is precipitated in a crystalline condition by theaddition of'sodium acetate.

Example II 7.5 grammes of 2-amino-4-methyl-thiazole-hydrochloride arefinely powdered and suspended in 15 c. c. dry pyridine and 13 grammes ofp-bromobenzene-sulphonyl chloride slowly added at a temperature of 30-40C. After heating for a few minutes on the steam bath to complete thereaction, the whole is poured into a large excess of water and theproduct ground with 50% aqueous acetic acid to remove gummy by-products.The 2- (p-bromo-benzene sulphonamido) -4-methylthiazole thus obtained isrecrystallised from diluted acetic acid and has M. Pt. 165-166 C.

The bromo compound is mixed with 10 volumes of 0.880 ammonia andone-twentieth of its weight of cuprous chloride and the mixture heatedin a closed vessel at 120 C. On filtration and removal of excess ofammonia by boiling, 2-(p-aminobenzene sulphonamido) 4-methyl thiazoleseparates after the removal of a little gummy impurity, and is purifiedby one of the methods described in Example IV.

Example III 28 grammes of azo-benzine-p-sulphonyl chloride is added to asuspension of 15 grammes of 2- amino-4-methyl-thiazole hydrochloride in50 c. c. dry pyridine without external cooling. The mixture is warmed onthe steam bath to complete the reaction and poured into water..Crystallisation from 80% acetic acid gives 2-(p-azo-benzensulphonamido)4-methyl-thiazole M. Pt. 208 C.

9 grammes of the azo compound are stirred with 30 c. c. of 2N.NaOH,diluted with warm water till solution is effected, and 9 grammes ofRaney nickel catalyst suspended in alcohol added. The mixture is shakenunder a pressure of hydrogen of 50 lbs/square inch until the theoreticalabsorption is attained. The catalyst is removed by filtration and onacidification with acetic acid Z-(p-amino-benzene sulphonamido)-4-methylthiazole separates in a practically pure state (M. Pt. 239-240C.)

Example IV To a solution of 114 grammes of -2-amino-4- methyl-thiazolein 250 c. c. of dry pyridine, 250 grammes ofp-acetylamino-benzenersulphonyl chloride is slowly added with stirringat a temperature of 50-60" C. The resulting reddishbrown syrupy solutionis then heated for 1 hour at 100 C. and poured into a mixture of 300 c.c.

. concentrated hydrochloric acid, 1 litre of water and 500 grammes ofice. The precipitated crude 2-(pacetylamino benzene sulphonamido)-4-methylthiazole is filtered off, washed with water and liberating thepure product by addition of acid.

The pure product is a white crystalline powder M, Pt. 240 C.-241 C,

Example V To 11.4 grammes of 2-amino-fi-methyl-thiazole (dissolved in 25c. c. of dry pyridine), 24 grammes of p-acetylamino-benzene-sulphonylchloride is slowly added. The temperature of the mixtur is allowed torise to 50-60 C. during the course of the addition and then raised to100 C. for fifteen minutes. When cool the whole is added to water andthe 2-(p-acetylamino-benzene-sulphonamido) -5-methyl-thiazole whichseparates is crystallised by solution in hot dilute sodium hydroxide andaddition of excess of acetic acid.

After boiling with volumes of 2N sodium hyc. c. pyridine.

droxlde for 45 minutes acidification with hot 50% acetic acidprecipitates 2-(p-aminobenzene-sulphonamido) -5-methyl thiazole. Theproduct is best purified by precipitation of its hydrochloride from itsaqueous solution by addition of sodium chloride. The hydrochloride isthen reconverted to the base (M. Pt. 243 C.) by boiling with diluteaqueous sodium acetate.

Example VI To 16.5 grammes of 2-amino-4:S-dimethyI-thiazolehydrochloride in 30 c. 0. dry pyridine is slowly added 40 grammes ofp-nitro-benzene-sulphonic anhydride, the temperature being kept below 60C. After heating for a few minutes on the steam bath, water is added andthe precipitated 2-(p-nitro-benzene sulphonamido) -425-dimethyl-thiazole recrystallised from acetic acid. The same product M.Pt. 232 C. (with decomposition) results from the action of 24 grammes ofp-nitrobenzene sulphonyl chloride under similar conditions.

5 grammes of the nitro compound are dissolved in 20 c. c.- of N.NaOH andthe solution added to a ferrous hydroxide paste made by the addition of10 grammes of caustic soda in 30 c. 0. water to a solution of 33 grammesof crystalline ferrous sulphate in c. 0. water. After warming for a fewminutes to coagulate the precipitated hydrated ferric oxide, the mixtureis filtered and the filtrate acidified with 50% aceticacid. Theprecipitated product is warmed with 15% hydrochloric acid, someinsoluble material removed by filtration and(2-aminobenzene-sulphonamido)- 4:5-dimethyl-thiazole precipitated by theaddition of sodium acetate. The product melts at 246 C.

Example VII 19 grammes of 2-amino-4-methyl-5-phenylthiazole is condensedwith 23.3 grammes of pacetylamino-benzene-sulphonyl chloride in 60 Thereaction mixture is poured into an excess of 10% hydrochloric acid andafter standing overnight is filtered ofl' and washed with water. Thecrude 2-p-acetylamino-benzene-sulphonamido-4-methyl-5-phenyl-thiazole ishydrolysed by boiling for 2 hours with 2N.NaOH. A small amount ofinsoluble material is removed by shaking with ether, the solutionacidified with acetic acid and the precipitate2-(p-amino-benzene-sulphonamido) -4-methyl-5-phenyl-thiazole purified bydissolving in ammonia, treating with charcoal, filtering, andreprecipitating with acetic acid. The pure product melts at C.(decomp.).

Example VIII 17.6 grammes of '2-amino-4-phenyl-thiazoie (Traumann Ann.249, 39) are dissolved in 45 c, c. of pyridine and 23.3 grammes ofp-acetylaminobenzene-sulphonyl chloride added with stirring during thecourse of half an hour. Reaction is completed by heating for 1 hour onthe water bath and the still warm reaction mixture poured into an excessof dilute HCl, the precipitate filtered off and washed. The product ishydrolysed by boiling with 2N.NaOH for 2 hours and the resultingsolution made acid with acetic acid. 2- (pamino-benzene sulphonamido) 4-phenyl-thiazole is precipitated and after purification by conversion tothe sodium salt, liberating the free acid and recrystallising, melts atC.

Example IX 53 grammes of 2-amino-4-methyl-5-hydroxyethyl-thiazoleprepared by the condensation of thiourea with3-chloro-3-acetopropan-1-oiis dissolved in 50 c. c. of water and 23.3grammes of p-acetylamino-benzene-sulphonylchloride is added withstirring over a period of half an hour at C. and stirring continued forabout 24-48 hours at the ordinary temperature. The product is filteredoff, washed with water. and hydrolysed by boiling with 15 times itsweight of 35% methane sulphonic acid for 3 minutes. .The solution isdiluted, neutralised with soda and re-acidified with dilute aceticiacid.The 2-(p-amino-benzenesulphonamido)-4-methyl-5 hydroxy-ethyl-thiazolemelts when rapidly heated at 141 or by slow heating at 174-176 C.

Example X 50% acetic acid. The 2-(p-acetylamino-benzenesulphonamido) 4methyl15-carbethoxy-thiazole so obtained has M. Pt. 249C. (withdecomposition) The acetylamino compound is boiled for 1 hours with tenvolumes of 15% hydrochloric acid and an equal volume of methanol. Oncooling 2- (p-amino-benzene-sulphonamido) 4 methyl-5-carbethoxy-thiazole hydrochloride M. Pt. 240? C. idecomp.) separates.This on treatment with sodium caibonate or sodium acetate gives the freebase which is purified by crystallisation from alcohol and then has M.Pt. 195 C. On hydrolysis with 2Ncaustic soda and acidifying with aceticacid '2 (p amino benzene-sulphonamido) 4 methyl 5-carboxy-thiazole isobtained M. Pt. 190 C. (decomp).

Example XI 21.4 grammes p-hcetylamino-benzene-sulphonamide and an equalweight of 2-bromo-benzthiazole are intimately mixed with the addition of'l grammes dry powdered potassium carbonate and 0.5 gramme copperbronze. The mixture so obtained is stirred for one hour at 200' C. underreflux. The melt is then lixiviated with water and required 2-(p-aminobenzene su1pl'ionamido)- benzthiazole then crystallises in colourlessplates M.Pt. 298 C. 1

Example XII 15.0 grammes of 2-amino-benzthiazole is dissolved in 50 c.c. pyridine and 24 grammes of pacetylamino-benzene-sulphonyl chlorideslowly added. When addition is complete the mixture is further heated at100 C. for a few minutes and poured into water. The precipitated crude2- (p acetylamino benzene-sulphonamido) benz-' thiazole are suspended in50 c. 0. dry P ridine and soda far 2 hours and'acidifled withconcentrated hydrochloric. acid. The product is2-(p-aminobenzene-sulphonamido) -benzthiazole M. Pt. 298

. Example XIII 19.4 grammes of 2-amino-6-ethoxy-benzthia zole dissolvedin 50 c. c. of dry pyridine are treated by the slow addition of 24grammes of p-acetylaminobenzene-sulphonyl chloride, the temperaturerising to 5060 C. After warming to com- "plete the reaction the mixtureis poured into water and the crude"2-(p-acetylamino-benzene-sulphonamido)-6-ethoxy--benzthiazole purifiedby solution in caustic alkali and reprecipitation from the hot solutionby excess of acetic acid. After a further crystallisation from 80%acetic acid it has M. Pt. 280-281 C.

The reprecipitated acetyl derivative is suspended in ten volumes ofalcohol and dry hydrochloric acid gas passed in to saturation. Onboiling, solution is eilected and in a short time the hydrochloride ofthe base separates. This is dissolved in methyl alcohol and thealcoholic solution added to an excess of sodium acetate in boilingaqueous solution. I

2-(p-aminobenzene-sulphonamide) 6 -ethoxybenzthiazole separates incolourless prisms M. Pt. 257 C.

Example XIV phonyl chloride. Solution is completed by heating on thesteam bath. The crude Z-(p-acetylamino-benzene-sulphonamido) 6-nitrobenzthiazole precipitated on addition of water is purified byextraction with 2N sodium hydroxide and acidification of the hotalkaline extract with 50% acetic acid. The purified product forms brightyellow prisms M. Pt. 303 C.

Hydrolysis of the acetyl group ensues on 30 minutes boiling with 10volumes of 2N caustic soda. The crude amino compound precipitated onacidification is purified by conversion to the hydrochloride by warmingwith 15% hydrochloric acid. The hydrochloride is filtered off dissolvedin'excess of ammonia and reprecitated by addition of acetic acid. Thepure Z-(p-aminu-benzenesulphonamido)-6-nitro-benzthiazole so obtainedmelts at 292 C.

Example XV ,benzene sulphonamido) -5-acetylamln0-benzthia-' zolecrystallised by addition of acetic acid to a hOt solution in dilutecaustic soda. Hydrolysis is eifected by boiling with 10 volumes-of 2Nsodium.

hydroxide for 40 minutes. Acidification with acetic acid thenprecipitates 2-(p-amino-benzene-sulphonamido) -5-amino-benzthiazole M.Pt. 270 C.

Example XVI 20.7 grammes of 2-amino-5-acetylamino-benztreated with 23grammes of p-nitrobenzene-sulphonyl chloride at 40-50 C. After warmingto complete the. reaction, the product is'precipitated aesasss bypouring into water and crystallised b oasis tion of hot acetic acid to ahot solution in dilute caustic soda.

The 2 (p nitrobenzene sulphonamido) acetylamino-benzthiazole formed ismixed with twice its weight of finely divided iron powder and themixture added to very dilute boiling acetic acid. After making Justalkaline with caustic soda and further boiling, ferric oxide is removedby filtration and the filtrate acidified with acetic acid. The crude 2-(p aminobenzene sulphonamido) -5-acetylamino-benzthiazole is purifiedby solution in a large excess of N-hydrochloric acid, followed byaddition of sodium acetate. After removal of a less pure fraction whilehot the pure product crystallises out on cooling. It melts at 265 C.

Example XVII 3.3 grammes of 2-(p-brom-benzene-sulphonamido)-4-methyl-thiazole are taken-up in c. c. of 2N sodium hydroxide andstirred with 2 c, c. methyl sulphate for 1 hour, further 2N sodiumhydroxide being added when necessary to ensure the alkalinity of themixture. On cooling in ice 2-(p-brom benzene sulphon methylamido) -4-methyl-thiazole separates and after two crystallisations from spirit hasM, Pt. 172 C.

Heated under pressure for 5 hours at 150 with 10 volumes of concentratedaqueous ammonia in the presence of /:i0 of its weight of cuprouschloride a solid product separates. After crystalli sation from methylalcohol pure 2-(p-amino-benzene-sulphon-methylamido) -4 methyl thiazoleM. Pt. 206 C. is obtained.

Example XVIII 23 grammes of 2-amino-5-methyl-th'iazole are dissolved in100 c. c. of pyridine and 46 grammes of p-nitrobenzene-sulphonylchloride slowly add ed. After heatin for minutes on the steam bath, themixture is poured into water and the precipitated 2-(p-nitro-benzene-sulphonamido-5- methyl-thiazole crystallised byaddition of its hot solution in caustic soda to a large excess ofboiling dilute acetic acid. The product M. Pt. 255 C. idec.) is taken upin N sodium hydroxide (2 mols) and boiled under reflux for 1 hour withan excess of ethyl iodide. The heavy oily layer which separates quicklycrystallises and the product 2-(p-nitro-benzene-sulphon ethylamido) 5-methyl-thiazole after recrystallisation from 80% alcohol melts at 175. v

- 4 grammes mixed with 8 grammes of fine iron powder is slowly added to150 c. c. boiling water containing a little acetic acid. The mixture ismade alkaline with ammonia and again boiled. Alcohol is then added tothe extent of about one quarter of the total volume and the hot mixturefiltered from iron oxide. 2-(p-amino-benzenesulphon-ethylamido)-5-methyl-thiazole immediately separates from the filtrate. Forpurification a few drops of 15% hydrochloric acid are added to asuspension of the base in hot alcohol. The solution so obtained onaddition of excess sodium acetate deposits the pure base M. Pt. l93 4C.7

Example XIX To a solution of 7.8 grammes ofZ-(p-acetylamino-benzene-sulphonamido) -4 methyl thiazole in 15 c. c. of2N NaOH is added c. o. of benzyl chloride with vigorous stirring whichis continued while the temperature is raised to 50 C. for one hour. Onevolume of water and two which separates. 2-(p-acetyl-amino-benzene-sulphon-benzylamido) -l-methyl-thiazole,purified by extraction with hot spirit and crystallisation from aceticacid; I

4.5 grammes of the product is boiled for Il /2 hours with 100 c. c. of15% hydrochloric acid and the hydrochloride which separates on coolingdecomposed by boiling with dilute aqueous sodium acetate. containingsome acetic acid. 2-(pamino-benzene-sulphon-benzylamido)-4-methylthiazole thus obtained after crystallisation from 90% alcoholhas M. Pt. 215-216 0.

Example XX addition. The crude 2 (p aminobenzene sul- (illphon-methylamido) -4-methyl thiazole obtained on filtration isrecrystallised from 80% alcohol. Iti sits at 205-206 C.

Example XXI 3.5 grammes of 2-(p-acetylamino-benzene-sulpbonamido)-benzthiazole are taken up in 25 c. c. of N, sodium hydroxide and thesolution stirred at room temperature with 2.5. c. c. of diethyl sulphatefor one hour. After standing. the solid which separates is well washedwith dilute sodium hydroxide and with water and finally boiled with 15c. c. of methylated spirit, cooled and filtered. The 2-(p acetyiaminobenzene sulphonethylamido) -benzthiazole so obtanied is then refluxedwith 20 volumes of 15% hydrochloride acid for one and a half hours andthe hydrochloride which separates on cooling removed by filtration. Thison boiling with equal volumes of alcohol and 15% aqueous ammonia givesthe required Z-(p-aminobenzene-sulphon-ethylamido) -benzthiazole whichafter crystallisation from alcohol has M. Pt. 209- 210 C. I

Example XXII 3.1 grammes of2-(p-amino-benzene-sulphenamido)-benzthiazole are dissolved in 25 c. c.of N. NaOH. 2.5 c. ,c. of diethyl sulphate added, and the mixturestirred vigorously for one hour. After standing. the crystals whichseparate are removed and washed with dilute sodium hydroxide and withwater. Repeated crystallisation from alcohol gives 2 (p aminobenzenesulphon ethylamido) -benzthiazo1e M. Pt. 209-210 C.

Example XXIII thiazole is precipitated in crystalline condition.

Melting point 254 C. (dec.).

5 grams of the product so obtained is suspended volumes of ether arethen added and the solid in 50 c. c. of water and dissolved by theaddition of 20 c. c. of 2N sodium hydroxide and 11 grams of sodiumhyposulphite slowly added with stirring and addition of further 2Nsodium hydroxide as necessary to maintain a clear solution. The mix-'-ture is heated in the steam bath for a few minutes to complete reaction,acidified strongly with hydrochloric acid and boiled for some minutes. vSulphur and other impurities are removed by filtration after furtherboiling with charcoal and the practically colourless solutionneutralised to 10 Congo red by. the addition or sodium acetate.

aasaaaa zenesulphonamido) -4 5 methyl 5 hydroxyethyl thiazole.

GEORGE NEWBERY.

